Medical Device for Dispersing Medicaments

ABSTRACT

For selective treatment of diseased tissue sections or organ parts, the surface of medical devices entering into contact with areas thereof under pressure is coated with lipophilic substantially water-insoluble medicaments binding to various tissue components with good adherence thereto, said medicaments having an effect thereupon a short time after entering into contact therewith without exerting a harmful influence upon adjacent healthy tissue.

This invention relates to a medical apparatus that releases drugs forthe selective therapy of specific tissues or organ parts and to a methodof manufacturing such drug-coated devices.

Numerous diseases do not affect the entire organism at the same time butare restricted to specific tissues, often even to very limitedindividual tissue areas or organ parts. Examples can be found amongtumor, joint and vascular diseases.

Pharmacotherapy of such diseases generally is effected by oral orintravenous administration of drugs that spread throughout the body andcause undesirable side effects in healthy tissues and organs, especiallywhen the disease to be treated is in a severe stage, which limit thetherapeutic application. The diseased tissues could be treated eitherselectively using drugs that specifically bind to diseased tissue (e.g.antibodies) while the administration path is maintained, or by selectiveadministration, e.g. direct injection into the diseased tissue or supplyvia a catheter to the blood vessels that feed the diseased tissue. Incase of selective administration may problems arise due to the shortperiod of time during which the drugs are efficacious and the invasiveadministration paths, as repeated administration is not an option. Whendrugs are selectively administered via the bloodstream that feeds thediseased tissue, there is the additional problem that the drugs areinsufficiently extracted when the blood or active agent solution swiftlyflows through the blood vessels.

These problems used to be addressed by various pharmaceuticalpreparations with sustained release of the active agent, drug-releasingimplants or selective access paths that stay operational for a longerperiod of time such as implanted catheters, etc.

It is known that the surface of medical equipment inserted into thebody, in particular, of catheters, can be coated with agents thatenhance gliding quality or prevent blood coagulation but have notherapeutic effect.

In addition, catheters are equipped with special devices for injectingdrugs into the arterial wall, for example, using needles or aperforation of the catheter wall that sits adjacent to the vessel walland through which the drug is injected at high pressure.

Other principles are based on extending the contact time between thearterial wall and an active agent preparation administered via thecatheter by either blocking the blood flow for a sufficient period. oftime, e. g. using dual balloon catheters in which the active agentsolution is contained in a chamber between the balloons, or by voidsbetween a toric outer wall of the balloon allowing a limited flow ofblood through a canal that passes through the balloon.

According to U.S. Pat. No. 5,102,402, drugs in the form of microcapsulesare inserted into preformed recesses of balloon catheters for delayedrelease of the active agent. When the balloon is inflated, themicrocapsules are to be pressed against the vessel wall, remain thereand slowly release the active agent(s). Many authors propose to applydrugs embedded in hydrogel onto balloon catheters while they do notspecify the function of the hydrogel, i. e. to act as an adhesive, toimprove the gliding quality, or for controlled drug release.

A disadvantage of the products mentioned above is their complexstructure, which causes production, quality control, and cost problemsand forces additional aggravating working steps on doctors and patientswhen applied. Some of the methods mentioned may result in undesirablevascular damage in excess of the intended dilatation of the vessel.Another setback is that each measure aimed at extending contact timeentails another reduction in blood and oxygen supply to the downstreamtissues.

For the sake of completeness, we also refer to a device for preventingrestenosis as described in WO 01/24866 that is coated with a lipidceramide substance derived from natural cell membranes. This substanceis used because of its affinity to cell walls that is not found incommon drugs. Experts in the field continue to state that restenosisprevention using drugs requires release of the active agent over aperiod of several days.

The problem underlying the present invention is to provide a device forthe release of drugs into specific tissue areas or organ parts that hasa strong therapeutic effect without damaging healthy tissue, which issufficiently well tolerated, and can be produced and applied with aminimal effort.

This problem is solved according to the invention by a device designedor produced in accordance with the characteristics of claims 1 and 15.The subordinate claims disclose further characteristics and advantageousimprovements of the invention.

The invention provides improved drug-carrying balloon catheters orsimilar medical devices manufactured in a simple process that are highlyversatile and facilitate the immediate release of active agents.Surprisingly, and contrary to the currently acknowledged opinion, nocontinuing release of the active agent from an inert matrix (polymer,hydrogel, microcapsule, etc.) and no special chemical or physical stateof the active ingredients is required or useful. Therefore, nosophisticated techniques for producing or controlling depot formulationsare required.

Coating balloons on catheters with drugs according to this invention isparticularly useful because there is a frequent need for treatment afterblood vessels or other passages in the body were dilated with balloonsto prevent stenosis or an occlusion of the lumen created by the pressureof the balloon, to limit tumor growth or to enhance healing processesincluding the formation of collateral circulation. This can be achievedby drugs that become effective in the immediate vicinity of the balloonsurface. The drugs firmly adhere to the balloon while passing througharteries with an intense blood flow on their way to their target untilthe balloon is inflated, and an effective dose is released in the shorttime (sometimes just a few seconds) during which the inflated balloon isin contact with the tissue, absorbed by the tissue in such a way thatthe blood flow that resumes immediately after the balloon is deflateddoes not rinse it off.

The subjects for coating are wires of the invention used to guidecatheters, needles and catheters or catheter parts that are pressedagainst the diseased tissue at least for a short time. Preferredcatheter materials are polyamides, polyamide mixtures and copolymers,polyethylene terephthalate, polyethylene and copolymers, polyurethane,natural rubber and its derivatives. The lengths and diameters of thecatheter or balloon areas designated for pharmacological treatment arenot of any decisive importance for their application as the dosage iscalculated in μg of active agent/mm² of surface area. For example,balloons with diameters ranging from 2 to 4 mm and lengths ranging from1.0 to 4.0 cm are commonly used for coronary dilatation. Balloons upto >20 mm in diameter and up to >10 cm in length can be used for othervessels. The surfaces to be coated may be smooth (i.e. without a specialstructure for absorbing the active agents), roughed up or comprise anystructure; while no special surface structures are required for theactive agents to adhere, such structures also do not impede adhesion.Adhesion of the active agents to the balloon surfaces is exclusivelycaused by selecting suitable solvents and, optionally, adding substancesthat influence adhesion. It is even surprisingly strong on completelysmooth balloon surfaces.

All surfaces can additionally be coated with substances that improve thegliding quality of the products, prevent blood from coagulating on thesurface or improve any other properties of these medical products havebut the materials used for coating do not have to be released into theenvironment and this additional coating does not noticeably reduce therelease of the active agents for treatment of the target tissue and thusthe product's efficacy.

Balloon catheters are formed by dilating a segment of 1 cm to ca. 10 cmlength of very thin plastic tubes. The dilated, very thin-wailed balloonmembrane is then folded several times along the catheter axis andwrapped tightly around the catheter axis so that the dilated area, whenfolded, is only slightly greater in diameter than the rest of thecatheter. The tight folding of the balloon membrane is required forpassing the balloon catheter through access ports, guiding catheters andheavily stenosed sections of blood vessels.

The balloons of catheters can be coated when folded or when unfolded.The process always provides an intact and sufficiently uniform surfacecoating, and the active agents adhere to the surface of the ballooncatheter even when it is refolded after being coated when unfolded.

A balloon that was coated when unfolded is produced without any impacton the coating, for example by using balloon membranes with preformedfolds and bends whose structure is not lost due to dilatation and whichallow the balloon membrane to refold at least loosely when the pressureis discharged from the balloon without requiring an external force asprimary cause. It is only after this prefolding that the preformed foldsare compressed by external pressure or by a vacuum. Folds are in no wayrequired to hold the active agent. In addition refolding can be achievedusing minor mechanical force by very smooth materials, and the toolsused may also be wetted by slippery biocompatible liquids in which theactive ingredients do not or, at least, do not well dissolve.

In accordance with another variant of the invention, the balloons ofreadily folded balloon catheters are coated by dipping them intolow-viscosity active agent solutions. Solvent and active agent penetrateinto the extremely dense folds where they form a surprisingly uniformcoat that contains a reproducible dose and is not damaged by anysubsequent step. The solution or, after the solvent has dried, the coatthat adheres to the outer surface may be left there or may be removed inanother step so that only the active agent portion that sits inside thefolds of the balloon is retained.

After coating, when the balloon is folded, a stent can be pulled overthe balloon catheter and firmly pressed onto it. The only step stillrequired is sterilization, e. g. using ethylene oxide.

The work cycle laid out like this is extremely simple, hardlysusceptible to failures, and can be carried out even with mechanically,chemically and physically sensitive coating materials. It was found thatcoating using this method does not result in any undesirable looseningor sticking together of the folds and that the active agent applied inthis way adheres firmly enough to not be rinsed off by the bloodstreambut releases most of the active agent when the balloon is inflated inthe target tissue.

Suitable drugs are lipophilic, mostly water-insoluble and stronglyacting drugs that bind to any tissue components. Drugs are calledlipophilic when their butanol to aqueous buffer solution (pH 7)distribution ratio is 0.5, preferably 1 and particularly preferred 5, orwhen their octanol to aqueous buffer solution (pH 7) distribution ratiois 1, preferably 10, and particularly preferred greater than 50.Alternatively, or in addition to this, the drugs should reversiblyand/or irreversibly bond to cell components at percentages greater than10%, preferably greater than 50%, and particularly preferred greaterthan 80%. Preferred are substances that inhibit cell proliferation orinflammatory processes, or antioxidants such as Paclitaxel and othertaxanes, Rapamycin and related substances, tacrolimus and relatedsubstances, corticoids, sexual hormones (estrogen, estradiol,antiandrogens) and related substances, statins, epothilones, probucol,prostacyclins, angiogenesis inducers, etc.

These substances are preferably present as a dry solid or as an oil onthe surfaces of the various medical products. Preferred are the smallestparticle sizes (mostly <5 microns, preferably <1 microns, particularlypreferred <0.1 microns), particularly preferred are amorphousnon-crystalline structures of the finest particle size that dissolvefast upon contact with tissue due to their large surface area anddespite the generally poor water-solubility of the drugs and do notfunction as microcapsules, i. e. dissolve spontaneously and fast. It issufficient that an effective dose is present in the form of smallest oramorphous particles; larger particles hardly contribute to the activeagent concentration in the tissue but do not cause any interference. Thedosage depends on the desired effect and the efficacy of the drug used.It may be up to 5 μg/mm² and this value does not even constitute anupper limit. It is easier to handle smaller dosages.

Good adhesion to the surfaces of catheters, needles or wires on animproved absorption by the tissues is achieved by embedding stronglylipophilic active agents with poor water solubility in a readilywater-soluble matrix substance. Suitable matrix substances arelow-molecular (molecular weight<5000 D, preferably<2000 D) hydrophilicsubstances such as contrast agents and dyes used in vivo for variousdiagnostic procedures in medicine, sugar and related substances such assugar alcohols, low-molecular polyethylene glycols, biocompatibleorganic and inorganic salts such as, for example, benzoates, salts andother derivatives of salicylic acid, etc. Examples of contrast agentsare iodinated X-ray contrast agents and paramagnetic chelates, examplesof dyes are indocyanine green, fluorescein, and methylene blue.Excipients may also improve shelf life of the products, cause specificadditional pharmacological effects or be instrumental for qualitycontrol.

In another embodiment of the invention, the pharmaceutical active agentscan be adsorbed to particles or applied to the surfaces of suitablemedical products with a low-molecular matrix. Suitable particles onceagain are diagnostics known to be biocompatible such as ferrites andvarious contrast agents for sonography.

Excipients of any kind can be used at lower or higher doses than theactive ingredients.

The medical products are coated using solutions, suspensions, oremulsions of the drugs and excipients mentioned above. Suitable mediafor solution, suspension or emulsion are, for example, ethanol,isopropanol, ethyl acetate, diethyl ether, acetone, dimethyl sulfoxide,dimethyl formamide, glycerin, water or mixtures thereof. Solventselection is based on the solubility of the active agents and adjuvants,the wetting of the surfaces to be coated and the effect on the structureof the coating and particles remaining after evaporation of the solvent,their adhesion to the surface and active agent transfer to the tissue invery short contact times.

Coating can be carried out by immersing, spreading, applying withdevices which deliver a defined volume to the surface or spraying atvarious temperatures and, optionally, vapor saturation of the solventsin the atmosphere. The procedure can be repeated several times usingdifferent solvents and excipients as may be required.

The balloons of folded balloon catheters ready for use can be given asurprisingly uniform, reproducible, dose-controllable coating withoutimpairing catheter functionality by immersing them in solutionscontaining the active agent(s) or by other measures. When the balloonsare repeatedly immersed in unsaturated active agent solutions, theactive agent applied previously is not completely stripped. off;instead, the active agent content of the balloons is increased in areproducible manner.

Excess solution or excess substances from the coating solution that areloosely attached to the exterior can be removed with simple methodswithout impairing the efficacy of the coating.

The various types of medical devices designed and manufactured accordingto the invention come into short-term contact with the tissue, i. e. fora few seconds, minutes, or hours. It is desirable in some cases topharmacologically treat the tissue with drugs in the immediate vicinityof the medical product, e. g. to prevent excess growth as a response toan injury or to reduce tumor growth, to enhance neovascularization ordiminish inflammatory reactions. In all these cases, high local drugconcentrations can be achieved for an astonishingly long time using themethod described above. A major advantage is the extraordinaryversatility of uses of the products and methods described.

A preferred application is to reduce hyperproliferation of vessel wallsinduced by dilatation with balloon catheters. This can be achieved whenstents are implanted by coating these stents with drugs, but only forthe vessel section covered by the stent. The coated balloon cathetersalso treat any areas at short distance in front of and just behind thestent that need treatment, they can treat the section where a stent hasbeen implanted without requiring another stent implantation and vesselsin which no stent is to be or can be implanted. An advantage as comparedto the stents that release a drug over a long period of time is improvedhealing and simultaneous good inhibition of hyperproliferation and areduced risk of thrombosis.

Several embodiments of the invention will be described below withreference to examples regarding the coating of balloon catheters,adhesion of the coating in the bloodstream, restenosis inhibition andactive agent content of the catheters.

EXAMPLE 1 Coating An Expanded Balloon Catheter With Paclitaxel In EthylAcetate

Balloon catheters made by BMT, Oberpfaffenhofen/Munich, Germany, productname Joker Lite, balloon dimensions 2.5 mm by 20 mm, are inflated to themaximum and immersed full length for 1 minute in ethyl acetate, 18.8 mgPaclitaxel per ml,+1% pharmaceutical olive oil, dried: Paclitaxelcontent 39 micrograms (after extraction with ethanol, HPLC).

EXAMPLE 2 Coating A Folded Balloon Catheter With Paclitaxel In EthylAcetate

Balloon catheters made by BMT, Oberpfaffenhofen/Munich, Germany, productname Joker Lite, balloon dimensions 2.5 mm by 20 mm, are immersed fulllength in folded condition for 1 minute in ethyl acetate, 18.8 mgPaclitaxel per ml,+1% pharmaceutical olive oil, and dried:

Paclitaxel content 69 micrograms.

EXAMPLE 3 Coating A Folded Balloon Catheter With Paclitaxel In EthylAcetate

a) Balloon catheters made by BMT, Oberpfaffenhofen/Munich, Germany,product name Joker Lite, balloon dimensions 2.5 mm by 20 mm, areimmersed full length in folded condition for 1 minute in ethyl acetate,16.6 mg Paclitaxel per ml, and dried for 4 hours:

-   -   Paclitaxel content 54 micrograms.

b) Same procedure, but additional two times immersed for 5 seconds with1 hour drying time after each immersion process in solution A (=3.33 mlethyl acetate+100.0 mg of Paclitaxel): Paclitaxel content 126micrograms.

c) Same procedure, but additional four times immersed for 5 seconds with1 hour drying time after each immersion process in the same solution:

-   -   Paclitaxel content 158 micrograms.

EXAMPLE 4 Coating A Balloon Catheter With Paclitaxel In Acetone

Dissolve 350 mg of Paclitaxel in 9.0 ml of acetone; balloon cathetersmade by BMT, Oberpfaffenhofen/Munich, Germany, product name Joker Lite,balloon dimensions 2.5 mm by 20 mm, are inflated to the maximum andimmersed full length for 1 minute and removed. The solvent is dried for12 hours at room temperature. Then the balloon is deflated and folded inthe common way using a PTFE-coated tool. Optionally, one can crimp astent of suitable dimensions onto the balloon: 29 micrograms ofPaclitaxel on the balloon.

EXAMPLE 5 Coating A Balloon Catheter With Paclitaxel In Acetone

a) Immersion of folded balloon catheters made by BMT, product nameAllegro, balloon dimensions 2.5 by 20 mm in a mixture of 0.15 mlethanol+4.5 μl of Ultravist 300 (an X-ray contrast agent made bySchering AG, Berlin, Germany)+1.35 ml of acetone+0.8 mg of Sudanred+30.0 mg of Paclitaxel:

-   -   The folded balloon sections of the catheters are immersed 5        times, the first time for one minute, then dried for 3 hours,        then 4 times at 1 hour intervals for 5 seconds each;        subsequently, a stent was crimped on and the catheter was        sterilized in the common way using ethylene oxide: Paclitaxel        content 172 micrograms, no decomposition products of the active        agent were determined using HPLC

b) A saturated aqueous mannitol solution is used instead of Ultravist300

c) A saturated aqueous sodium salicylate solution (pH 7.5) is usedinstead of Ultravist 300

d) 5 mg of acetylsalicylic acid are added to the completed solutionaccording to (5a).

e) 5 mg of glycerin are added to the completed solution according to(5a).

EXAMPLE 6 Adhesion Of The Active Agent In The Bloodstream

12 balloon catheters made by BMT, product name Allegro, balloondimensions 2.5 by 20 mm, were used. The folded balloon sections of 6catheters each were either 5 times immersed in [0.15 ml of ethanol+4.5μl of Ultravist 300+1.35 ml of acetone 0.8 mg of Sudan red+30.0 mgPaclitaxel] or 5 times in [1.5 ml of ethyl acetate+0.8 my Sudan red+31.0mg Paclitaxel], the first time for 1 minute each with 3 hours of dryingtime, then 4 times for 5 seconds each at 1 hour intervals; then 3 of thefolded balloons of each group were gently moved for 5 minutes at 37° C.in 50 ml of human blood and removed to determine the Paclitaxel content:Reduction of mean values (n=3 per coating method) by 5 minutes ofmovement in blood as compared to 3 control catheters that were notincubated in blood.

-   -   Acetone: 12%    -   Ethyl acetate: 10%

EXAMPLE 7 Examination Of Restenosis Inhibition After Angioplasty AndStent Implantation In Coronary Arteries Of Pigs

Folded balloon catheters of the Joker Lite type made by BMT, 3,5 by 20mm or 3.0 by 20 mm were immersed for 1 minute either in

solution A) 3.33 ml of ethyl acetate (EA)+100.0 mg of Paclitaxel, or in

solution B) 0.45 ml of ethanol+100 μL of Ultravist-370+4.5 ml acetone(ac)+150.0 mg Paclitaxel

and dried over night at room temperature. One more (low dose=L) or 4more (high dose=H) immersion process(es), respectively, were carried outfor just five seconds at 1 hour intervals on the next day.

Active agent content after 2 immersions in solution (B) averaged 250 μg,after 5 immersions in solution (B) 500 μg, in solution (A) 400 μg.

The catheters coated with Paclitaxel or uncoated were used to implantstents into the left anterior or lateral coronary artery of a total of22 pigs, and the vessels were slightly overdilated to stimulaterestenosis by tissue hyperplasia. The animals were reangiographed after5 weeks, and the vessel stenosis shown in the angiograms was measuredusing an automatic computer program.

Group Stenosis (%) Uncoated 50.49 AcL 20.22 EAH 36.01 AcH 0.86 P .004

Quantitative coronary angiography 5 weeks after stent implantation withuncoated and coated catheters; stenosis=reduction of lumen diameter inpercent in the area of the stent as compared to the lumen diameterimmediately after stent implantation; mean value and statisticalsignificance of the effect of treatment.

EXAMPLE 8 Active Agent Content Of The Catheters After Vessel DilatationAnd Stent Implantation

After stent implantation and removal from the animals, the balloons fromExample 8 ca. 3 cm in length were cut off the balloon catheters andplaced in 1.5 ml of ethanol. Paclitaxel content was determined usingHPLC. All available coated balloons and a selection of uncoated balloonswere examined.

Coronary,

3.0 by 20 mm, coating: Ac high  38 ± 4 μg (n = 4) Ac low  22 ± 5 μg (n =2) EEE high  41 (n = 1) 3.5 by 20 mm, coating: Ac high  37 ± 10 μg (n =8) Ac low  26 ± 6 μg (n = 8) EEE high  53 ± 9 μg (n = 9) Uncoated 0.9 ±1.0 μg (n = 7) (independent of size and vessel area)

It follows from Example 6 that a maximum of 10% of the dose is lostbefore the balloon is inflated and about 10% of the dose remain on theballoon.

EXAMPLE 9

Probucol is added to acetone at a concentration of 100 mg per ml; thesolution is used to coat balloon catheters as described in the aboveexamples.

EXAMPLE 10

Rapamycin is dissolved at a concentration of 10 mg/ml in diethyl ether.The balloon sections of the catheters are coated as described in theabove examples; after removal from the coating solution, the balloonsshould be brought into a horizontal position and continuously be turnedaround their longitudinal axis as soon as possible.

EXAMPLE 11

Epothilone B is dissolved in ethyl acetate at a concentration of 2mg/ml; the solution is used to coat balloon catheters as described inthe above examples.

1-23. (canceled)
 24. A medical device comprising a balloon having aballoon surface comprising paclitaxel and a sugar alcohol on the balloonsurface.
 25. The medical device of claim 24 wherein said medical devicefurther comprises a stent.
 26. The medical device of claim 24 whereinthe balloon surface has preformed longitudinal folds maintaining aninclination to refold after inflation.
 27. The medical device of claim26 wherein at least an area covered by the folds is covered with thepaclitaxel.
 28. The medical device of claim 26 wherein only an areacovered by the folds is covered sith the paclitaxel.
 29. The medicaldevice of claim 24 wherein the balloon surface consists of a material towhich the paclitaxel and sugar alcohol adhere sufficiently well toresist forces required for folding, essentially without damage.
 30. Themedical device of claim 24 wherein the paclitaxel and sugar alcohol arepresent as a dry solid on the balloon surface.
 31. The medical device ofclaim 24 wherein the concentration of paclitaxel on said surface is upto 5 μg/mm².